Functional Lung Regions Research Articles

Deriving Pulmonary Ventilation Images From Clinical 4D-CBCT Using a Deep Learning-Based Model.

PurposeThe current algorithms for measuring ventilation images from 4D cone-beam computed tomography (CBCT) are affected by the accuracy of deformable image registration (DIR). This study proposes a new deep learning (DL) method that does not rely on DIR to derive ventilation images from 4D-CBCT (CBCT-VI), which was validated with the gold-standard single-photon emission-computed tomography ventilation image (SPECT-VI).Materials and MethodsThis study consists of 4D-CBCT and 99mTc-Technegas SPECT/CT scans of 28 esophagus or lung cancer patients. The scans were rigidly registered for each patient. Using these data, CBCT-VI was derived using a deep learning-based model. Two types of model input data are studied, namely, (a) 10 phases of 4D-CBCT and (b) two phases of peak-exhalation and peak-inhalation of 4D-CBCT. A sevenfold cross-validation was applied to train and evaluate the model. The DIR-dependent methods (density-change-based and Jacobian-based methods) were used to measure the CBCT-VIs for comparison. The correlation was calculated between each CBCT-VI and SPECT-VI using voxel-wise Spearman’s correlation. The ventilation images were divided into high, medium, and low functional lung regions. The similarity of different functional lung regions between SPECT-VI and each CBCT-VI was evaluated using the dice similarity coefficient (DSC). One-factor ANONA model was used for statistical analysis of the averaged DSC for the different methods of generating ventilation images.ResultsThe correlation values were 0.02 ± 0.10, 0.02 ± 0.09, and 0.65 ± 0.13/0.65 ± 0.15, and the averaged DSC values were 0.34 ± 0.04, 0.34 ± 0.03, and 0.59 ± 0.08/0.58 ± 0.09 for the density change, Jacobian, and deep learning methods, respectively. The strongest correlation and the highest similarity with SPECT-VI were observed for the deep learning method compared to the density change and Jacobian methods.ConclusionThe results showed that the deep learning method improved the accuracy of correlation and similarity significantly, and the derived CBCT-VIs have the potential to monitor the lung function dynamic changes during radiotherapy.

Investigating the SPECT Dose-Function Metrics Associated With Radiation-Induced Lung Toxicity Risk in Patients With Non-small Cell Lung Cancer Undergoing Radiation Therapy

PurposeDose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT).Methods and MaterialsSPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT.ResultsBy analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk.ConclusionsIrradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.

The impact of 4DCT-ventilation imaging-guided proton therapy on stereotactic body radiotherapy for lung cancer

Functional lung avoidance during radiotherapy can help reduce pulmonary toxicity. This study assessed the potential impact of four-dimensional computed tomography (4DCT)-ventilation imaging-guided proton radiotherapy (PT) on stereotactic body radiotherapy (SBRT) by comparing it with three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT), which employ photon beams. Thirteen lung cancer patients who received SBRT with 3D-CRT were included in the study. 4DCT ventilation was calculated using the patients’ 4DCT data, deformable image registration, and a density-change-based algorithm. Three functional treatment plans sparing the functional lung regions were developed for each patient using 3D-CRT, VMAT, and PT. The prescribed doses and dose constraints were based on the Radiation Therapy Oncology Group 0618 protocol. We evaluated the region of interest (ROI) and functional map-based dose-function metrics for 4DCT ventilation and the irradiated dose. Using 3D-CRT, VMAT, and PT, the percentages of the functional lung regions that received ≥ 5 Gy (fV5) were 26.0%, 21.9%, and 10.7%, respectively; the fV10 were 14.4%, 11.4%, and 9.0%, respectively; and fV20 were 6.5%, 6.4%, and 6.6%, respectively, and the functional mean lung doses (fMLD) were 5.6 Gy, 5.2 Gy, and 3.8 Gy, respectively. These results indicated that PT resulted in a significant reduction in fMLD, fV5, and fV10, but not fV20. The use of PT reduced the radiation to highly functional lung regions compared with those for 3D-CRT and VMAT while meeting all dose constraints.

Single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging for radiotherapy planning in patients with lung cancer: a meta-analysis

Functional imaging modalities enable practitioners to identify functional lung regions. This analysis evaluated the feasibility of nuclear medicine imaging to avoid doses to the functional lung in radiotherapy (RT) planning for patients with lung cancer. This systematic review and meta-analysis was carried out according to PRISMA-P guidelines. A search of EMBASE and PubMed for studies published throughout the last 20 years was performed using the following search criteria: (a) ‘lung cancer’ or ‘lung malignancy’ and (b) ‘radiotherapy’ or ‘radiation therapy’ or ‘RT planning’ and (c) ‘SPECT’ or ‘single positron emission computed tomography’ or ‘functional image.’ The analyzed planning parameters were the volumes of the normal lung that have received ≥ 10 Gy and ≥ 20 Gy of radiation (V10 and V20, respectively) and the mean lung dose (MLD). We compared the planning parameters obtained from anatomical RT planning and functional RT planning using perfusion or ventilation imaging (‘V10, V20 or MLD’ in anatomical plan vs. ‘fV10, fV20 or fMLD’ in functional plan). A total of 309 patients with 344 RT plan sets from 15 publications (11 perfusion SPECT, 2 ventilation SPECT, and 1 SPECT and 1 PET with both perfusion and ventilation) were included in the meta-analysis. The standard mean differences in planning parameters in functional plans using nuclear imaging were significantly reduced compared to those of anatomical plans (P < 0.01 for all): − 0.42 (95% confidence interval (CI) − 0.78 to − 0.07) for ‘V10 vs. fV10′, − 0.41 (95% CI − 0.64 to − 0.17) for ‘V20 vs. fV20′, and − 0.24 (95% CI − 0.45 to − 0.03) for ‘MLD vs. fMLD’. In subgroup analysis, the functional plan using perfusion was significantly lower than the anatomical plan in all planning parameters, but there was no significant difference for ventilation. RT planning with nuclear functional lung imaging has potential to reduce radiation-induced lung injury. Perfusion imaging seems to be more promising than ventilation imaging for all planning parameters. There were not enough studies using ventilation imaging to determine what the effect is on the lung plan parameters.

Functionally weighted airway sparing (FWAS): a functional avoidance method for preserving post-treatment ventilation in lung radiotherapy

Recent changes to the guidelines for screening and early diagnosis of lung cancer have increased the interest in preserving post-radiotherapy lung function. Current investigational approaches are based on spatially mapping functional regions and generating regional avoidance plans that preferentially spare highly ventilated/perfused lung. A potentially critical, yet overlooked, aspect of functional avoidance is radiation injury to peripheral airways, which serve as gas conduits to and from functional lung regions. Dose redistribution based solely on regional function may cause irreparable damage to the ‘supply chain’. To address this deficiency, we propose the functionally weighted airway sparing (FWAS) method. FWAS (i) maps the bronchial pathways to each functional sub-lobar lung volume; (ii) assigns a weighting factor to each airway based on the relative contribution of the sub-volume to overall lung function; and (iii) creates a treatment plan that aims to preserve these functional pathways. To evaluate it, we used four cases from a retrospective cohort of SAbR patients treated for lung cancer. Each patient’s airways were auto-segmented from a diagnostic-quality breath-hold CT using a research virtual bronchoscopy software. A ventilation map was generated from the planning 4DCT to map regional lung function. For each terminal airway, as resolved by the segmentation software, the total ventilation within the sub-lobar volume supported by that airway was estimated and used as a function-based weighting factor. Upstream airways were weighted based on the cumulative volumetric ventilation supported by corresponding downstream airways. Using a previously developed model for airway radiosensitivity, dose constraints were determined for each airway corresponding to a <5% probability of airway collapse. Airway dose constraints, ventilation scores, and clinical dose constraints were input to a swarm optimization–based inverse planning engine to create a 3D conformal SAbR plan (CRT). The FWAS plans were compared to the patients’ prescribed CRT clinical plans and the inverse-optimized clinical plans. Depending on the size and location of the tumour, the FWAS plan showed superior preservation of ventilation due to airflow preservation through open pathways (i.e. cumulative ventilation score from the sub-lobar volumes of open pathways). Improvements ranged between 3% and 23%, when comparing to the prescribed clinical plans, and between 3% and 35%, when comparing to the inverse-optimized clinical plans. The three plans satisfied clinical requirements for PTV coverage and OAR dose constraints. These initial results suggest that by sparing pathways to high-functioning lung subregions it is possible to reduce post-SAbR loss of respiratory function.

The impact of 4DCT-ventilation imaging-guided proton therapy on stereotactic body radiotherapy for lung cancer.

Functional lung avoidance during radiotherapy can help reduce pulmonary toxicity. This study assessed the potential impact of four-dimensional computed tomography (4DCT)-ventilation imaging-guided proton radiotherapy (PT) on stereotactic body radiotherapy (SBRT) by comparing it with three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT), which employ photon beams. Thirteen lung cancer patients who received SBRT with 3D-CRT were included in the study. 4DCT ventilation was calculated using the patients' 4DCT data, deformable image registration, and a density-change-based algorithm. Three functional treatment plans sparing the functional lung regions were developed for each patient using 3D-CRT, VMAT, and PT. The prescribed doses and dose constraints were based on the Radiation Therapy Oncology Group 0618 protocol. We evaluated the region of interest (ROI) and functional map-based dose-function metrics for 4DCT ventilation and the irradiated dose. Using 3D-CRT, VMAT, and PT, the percentages of the functional lung regions that received ≥ 5Gy (fV5) were 26.0%, 21.9%, and 10.7%, respectively; the fV10 were 14.4%, 11.4%, and 9.0%, respectively; and fV20 were 6.5%, 6.4%, and 6.6%, respectively, and the functional mean lung doses (fMLD) were 5.6Gy, 5.2Gy, and 3.8Gy, respectively. These results indicated that PT resulted in a significant reduction in fMLD, fV5, and fV10, but not fV20. The use of PT reduced the radiation to highly functional lung regions compared with those for 3D-CRT and VMAT while meeting all dose constraints.

Image-based lung functional radiotherapy planning for non-small cell lung cancer.

This simulation study assessed the feasibility and impact of incorporating additional information from lung perfusion single-photon emission computed tomography (SPECT) into intensity-modulated radiotherapy planning for the treatment of non-small cell lung cancer (NSCLC). In this simulation study, data of 13patients with stageI-III NSCLC previously treated by radio(chemo)therapy were used. The SPECT was fused together with radiotherapy planning CT. Functional lung regions (FL) and non-functional lung regions (nFL) were defined based on SPECT images. Four treatment plans were created for each patient: an IMRT and aVMAT plan with planning CT (anatomical plans), and an IMRT and aVMATplan which integrate the additional information from lung perfusion scintigraphy (function plans). Dosimetric parameters were compared between all plans for PTV parameters and normal tissue preservation, focusing on optimizing the lung volume receiving at least 20 Gy (V20Gy). Compared to anatomical plans, functional IMRT and functional VMAT plans reduced functional lung V20Gy in all cases of local and diffuse hypoperfusion patterns of SPECT defects. Similar results were observed for functional lung V30Gy and median dose to functional lung Dmean, but were not statistically significant in any group. Asignificant increase in non-functional lung V20Gy resulted in both functional plans. There were no significant differences in conformity or heterogeneity indices or PTV median doses between either pair of anatomical and functional plans. The incorporation of functional imaging for radiotherapy planning in non-small cell lung cancer is feasible and appears to be beneficial in preserving afunctional lung in non-small cell lung cancer.

Regional lung avoidance by CT numbers to reduce radiation-induced lung damage risk in non-small–cell lung cancer: a simulation study

Background: Selective avoidance aims at sparing functional lung regions. Here, we preferentially direct radiation to irreversibly nonfunctional lung areas based on planning CT imaging to reduce functional lung damage.Materials and methods: For 12 stage I-IV NSCLC patients, 5 lung substructures were segmented on the planning CT, combining voxels <–900HU, –900HU to –801HU, –800HU to –701HU, –700HU to –601HU and ≥–600HU (Level 1 to 5). Two VMAT plans were optimized: a reference plan blinded from substructures and a selective avoidance plan (AV) imposing gradually stricter constraints on Level 1–5, based on previously validated associations between lung subvolume baseline density and density increase (ΔHU) after treatment. Characteristics of treatment plans were evaluated, including subvolumes, dose, and predicted ΔHU (with reported 95% CI reflecting prediction model uncertainty).Results: Segmented substructures were on average 477 cc, 1157 cc, 484 cc, 69 cc, and 123 cc (Level 1–5). AV plans could spare Level 3–5, e.g., mean dose decrease of 3.5 Gy (range 0.6 Gy; 6.0 Gy) for Level 5, p<.001. This significantly reduced the average lung mass with predicted ΔHU>20HU by 12.5 g (95% CI: 5.4–16.9) and 27.1 g (95% CI: 10.2–32.9) for a median and upper 10th percentile patient susceptibility for damage simulation, respectively.Conclusions: Lung damage avoidance based on CT density is feasible and easy to implement. A biomarker providing a reliable selection of patients with high susceptibility for lung damage will be crucial to show the clinical relevance of this avoidance planning strategy.

Incorporating 4DCT-Based Elasticity Information As a Regional Physiological Representation for Function Preserving Lung SBRT Treatment Planning

Recent advancements in radiotherapy treatment delivery techniques have led to the ability to develop treatment plans that can intelligently spare the most functional normal tissue. Specifically, for lungs, such a treatment plan can greatly improve patient’s quality of life. There is a need for a CT-based lung functional biomarker that can be used for function-preserving treatment planning to reduce lung toxicity after radiation therapy. Lung tissue elasticity has been shown to correlate with overall lung tissue function. The purpose of this study is to investigate the feasibility of avoiding functional lung regions characterized by 4DCT-derived lung tissue elasticity to minimize functional lung dose during stereotactic body radiotherapy (SBRT) treatment planning. 4DCT-based lung elastography was used to retrospectively derive elasticity information for 7 lung cancer patients treated with SBRT. All patients had early and late stage COPD as classified by GOLD 2017. Functional lung tissue was empirically determined to be the lung parenchymal tissue with elastic moduli between 4 and 8 kPa. Clinical and functional avoidance SBRT plans were developed, with the latter having additional constraints in order to preferentially spare the functional lung tissue. Plans were accepted once they met all TG-101 normal tissue constraints. The plan quality was evaluated for both clinical and functional plans by comparing target coverage and max OAR dose. Dose-volume and dose-function metrics were also investigated. Functional-avoidance plans were able to evade functional lung regions while maintaining target coverage and strict normal tissue constraints. While the plan quality was similar between functional and clinical plans, dose volume and dose function metrics illustrated a decrease in dose to functional and total lung volumes. More improvements in the planned dose distributions were seen in patients with mild stage COPD as compared to late stage COPD patients. With lung tissue elasticity providing patient-specific maps of spatial function and physiology, clinically relevant function-preserving SBRT plans were developed for 7 patients. This study has shown that is feasible to develop functional-tissue sparing SBRT plans that preferentially spare the functional lung tissue while maintaining clinically acceptable plan quality. The avoidance of elasticity-defined functional lung tissue in radiotherapy has the potential to lead to less radiation-induced toxicity after radiotherapy treatment, and better patient quality of life.

Functional perfusion image guided radiation treatment planning for locally advanced lung cancer

Background and purposeFunctional avoidance radiation therapy (RT) aims at sparing functional lung regions. The purpose of this simulation study was to evaluate the feasibility of functional lung avoidance methodology in RT of lung cancer and to characterize the achievable dosimetry of single photon emission computed tomography (SPECT) guided treatment planning.Materials and methodsFifteen consecutive lung cancer patients were included and planned for definitive RT of 60–66 Gy in 2-Gy fractions. Two plans were optimized: a standard CT-plan, and functional SPECT-plan. The objective was to reduce dose to the highly functional lung subvolumes without compromising tumour coverage, and respecting dose to other organs at risk. For each patient a 3D-conformal, intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy plans were created for standard and functional avoidance. Standard versus functional dose-volume parameters for functional lung (FL) subvolumes, organs at risk and tumour coverage were compared.ResultsThe largest dose reduction was achieved with IMRT plans. Functional plans resulted in dose reduction from 9.0 Gy to 6.7 Gy (mean reduction of 2.3 Gy or 26%) to the highest functional subvolume FL80% (95%CI 1.1; 3.5). Dose to FL40% was reduced from 13.3 Gy to 11.6 Gy with functional planning. Dose reduction to FL40% was 1.7 Gy (95%CI 0.9; 2.6). Functional volume of lung receiving over 20 Gy improved by 5% (standard 22%, functional 17%). Dose to organs at risk and tumour coverage were not significantly different between plans.ConclusionsSPECT/CT-guided planning resulted in improved dose-volumetric outcomes for functional lung. This methodology may lead to potential reduction in radiation-induced lung toxicity.

4DCT Ventilation Map Construction Using Biomechanics-base Image Registration and Enhanced Air Segmentation.

Current lung radiation therapy (RT) treatment planning algorithms used in most centers assume homogeneous lung function. However, co-existing pulmonary dysfunctions present in many non-small cell lung cancer (NSCLC) patients, particularly smokers, cause regional variations in both perfusion and ventilation, leading to inhomogeneous lung function. An adaptive RT treatment planning that deliberately avoids highly functional lung regions can potentially reduce pulmonary toxicity and morbidity. The ventilation component of lung function can be measured using a variety of techniques. Recently, 4DCT ventilation imaging has emerged as a cost-effective and accessible method. Current 4DCT ventilation calculation methods, including the intensity-based and Jacobian models, suffer from inaccurate estimations of air volume distribution and unreliability of intensity-based image registration algorithms. In this study, we propose a novel method that utilizes a biomechanical model-based registration along with an accurate air segmentation algorithm to calculate 4DCT ventilation maps. The results show a successful development of ventilation maps using the proposed method.

Single-energy computed tomography-based pulmonary perfusion imaging: Proof-of-principle in a canine model.

Purpose:Radiotherapy (RT) that selectively avoids irradiating highly functional lung regions may reduce pulmonary toxicity, which is substantial in lung cancer RT. Single-energy computed tomography (CT) pulmonary perfusion imaging has several advantages (e.g., higher resolution) over other modalities and has great potential for widespread clinical implementation, particularly in RT. The purpose of this study was to establish proof-of-principle for single-energy CT perfusion imaging.Methods:Single-energy CT perfusion imaging is based on the following: (1) acquisition of end-inspiratory breath-hold CT scans before and after intravenous injection of iodinated contrast agents, (2) deformable image registration (DIR) for spatial mapping of those two CT image data sets, and (3) subtraction of the precontrast image data set from the postcontrast image data set, yielding a map of regional Hounsfield unit (HU) enhancement, a surrogate for regional perfusion. In a protocol approved by the institutional animal care and use committee, the authors acquired CT scans in the prone position for a total of 14 anesthetized canines (seven canines with normal lungs and seven canines with diseased lungs). The elastix algorithm was used for DIR. The accuracy of DIR was evaluated based on the target registration error (TRE) of 50 anatomic pulmonary landmarks per subject for 10 randomly selected subjects as well as on singularities (i.e., regions where the displacement vector field is not bijective). Prior to perfusion computation, HUs of the precontrast end-inspiratory image were corrected for variation in the lung inflation level between the precontrast and postcontrast end-inspiratory CT scans, using a model built from two additional precontrast CT scans at end-expiration and midinspiration. The authors also assessed spatial heterogeneity and gravitationally directed gradients of regional perfusion for normal lung subjects and diseased lung subjects using a two-sample two-tailed t-test.Results:The mean TRE (and standard deviation) was 0.6 ± 0.7 mm (smaller than the voxel dimension) for DIR between pre contrast and postcontrast end-inspiratory CT image data sets. No singularities were observed in the displacement vector fields. The mean HU enhancement (and standard deviation) was 37.3 ± 10.5 HU for normal lung subjects and 30.7 ± 13.5 HU for diseased lung subjects. Spatial heterogeneity of regional perfusion was found to be higher for diseased lung subjects than for normal lung subjects, i.e., a mean coefficient of variation of 2.06 vs 1.59 (p = 0.07). The average gravitationally directed gradient was strong and significant (R2 = 0.99, p < 0.01) for normal lung dogs, whereas it was moderate and nonsignificant (R2 = 0.61, p = 0.12) for diseased lung dogs.Conclusions:This canine study demonstrated the accuracy of DIR with subvoxel TREs on average, higher spatial heterogeneity of regional perfusion for diseased lung subjects than for normal lung subjects, and a strong gravitationally directed gradient for normal lung subjects, providing proof-of-principle for single-energy CT pulmonary perfusion imaging. Further studies such as comparison with other perfusion imaging modalities will be necessary to validate the physiological significance.

SU‐C‐BRA‐06: Developing Clinical and Quantitative Guidelines for a 4DCT‐Ventilation Functional Avoidance Clinical Trial

Purpose:4DCT‐ventilation is an exciting new imaging modality that uses 4DCTs to calculate lung ventilation. Because 4DCTs are acquired as part of routine care, calculating 4DCT‐ventilation allows for lung function evaluation without additional cost or inconvenience to the patient. Development of a clinical trial is underway at our institution to use 4DCT‐ventilation for thoracic functional avoidance with the idea that preferential sparing of functional lung regions can decrease pulmonary toxicity. The purpose of our work was to develop the practical aspects of a 4DCT‐ventilation functional avoidance clinical trial including: 1.assessing patient eligibility 2.developing trial inclusion criteria and 3.developing treatment planning and dose‐function evaluation strategies.Methods:96 stage III lung cancer patients from 2 institutions were retrospectively reviewed. 4DCT‐ventilation maps were calculated using the patient's 4DCTs, deformable image registrations, and a density‐change‐based algorithm. To assess patient eligibility and develop trial inclusion criteria we used an observer‐based binary end point noting the presence or absence of a ventilation defect and developed an algorithm based on the percent ventilation in each lung third. Functional avoidance planning integrating 4DCT‐ventilation was performed using rapid‐arc and compared to the patient's clinically used plan.Results:Investigator‐determined clinical ventilation defects were present in 69% of patients. Our regional/lung‐thirds ventilation algorithm identified that 59% of patients have lung functional profiles suitable for functional avoidance. Compared to the clinical plan, functional avoidance planning was able to reduce the mean dose to functional lung by 2 Gy while delivering comparable target coverage and cord/heart doses.Conclusions:4DCT‐ventilation functional avoidance clinical trials have great potential to reduce toxicity, and our data suggest that 59% of lung cancer patients have lung function profiles suitable for functional avoidance. Our study used a retrospective evaluation of a large lung cancer patient database to develop the practical aspects of a 4DCT‐ventilation functional avoidance clinical trial.(R.C., E.C., T.G.), NIH Research Scientist Development Award K01‐CA181292 (R.C.), and State of Colorado Advanced Industries Accelerator Grant (Y.V.).

Optimal beam arrangement for pulmonary ventilation image-guided intensity-modulated radiotherapy for lung cancer.

BackgroundThe principal aim of this study was to evaluate the feasibility of incorporating four-dimensional (4D)-computed tomography (CT)-based functional information into treatment planning and to evaluate the potential benefits of individualized beam setups to better protect lung functionality in patients with non-small cell lung cancer (NSCLC).MethodsPeak-exhale and peak-inhale CT scans were carried out in 16 patients with NSCLC treated with intensity-modulated radiotherapy (IMRT). 4D-CT-based ventilation information was generated from the two sets of CT images using deformable image registration. Four kinds of IMRT plans were generated for each patient: two anatomic plans without incorporation of ventilation information, and two functional plans with ventilation information, using either five equally spaced beams (FESB) or five manually optimized beams (FMOB). The dosimetric parameters of the plans were compared in terms of target and normal tissue structures, with special focus on dose delivered to total lung and functional lung.ResultsIn both the anatomic and functional plans, the percentages of both the functional and total lung regions irradiated at V5, V10, and V20 (percentage volume irradiated to >5, >10 and >20 Gy, respectively) were significantly lower for FMOB compared with FESB (P < 0.05), but there was no significant difference for V30 (P > 0.05). Compared with FESB, a greater degree of sparing of the functional lung was achieved in functional IMRT plans with optimal beam arrangement, without compromising target volume coverage or the irradiated volume of organs at risk, such as the spinal cord, esophagus, and heart.ConclusionsPulmonary ventilation image-guided IMRT planning with further optimization of beam arrangements improves the preservation of functional lung in patients with NSCLC.

Changes in Functional Lung Regions During the Course of Radiation Therapy and Their Potential Impact on Lung Dosimetry for Non-Small Cell Lung Cancer

To study changes in functional activity on ventilation (V)/perfusion (Q) single-photon emission computed tomography (SPECT) during radiation therapy (RT) and explore the impact of such changes on lung dosimetry in patients with non-small cell lung cancer (NSCLC). Fifteen NSCLC patients with centrally located tumors were enrolled. All patients were treated with definitive RT dose of ≥60 Gy. V/Q SPECT-CT scans were performed prior to and after delivery of 45 Gy of fractionated RT. SPECT images were used to define temporarily dysfunctional regions of lung caused by tumor or other potentially reversible conditions as B3. The functional lung (FL) was defined on SPECT by 2 separate approaches: FL1, a threshold of 30% of the maximum uptake of the patient's lung; and FL2, FL1 plus B3 region. The impact of changes in FL between initiation of RT and delivery of 45 Gy on lung dosimetry were analyzed. Fourteen patients (93%) had larger FL2 volumes than FL1 pre-RT (P<.001). Dysfunctional lung became functional in 11 patients (73%) on V SPECT and in 10 patients (67%) on Q SPECT. The dosimetric parameters generated from CT-based anatomical lung had significantly lower values in FL1 than FL2, with a median reduction in the volume of lung receiving a dose of at least 20 Gy (V20) of 3%, 5.6%, and mean lung dose of 0.95 and 1.55 on V and Q SPECT respectively. Regional ventilation and perfusion function improve significantly during RT in centrally located NSCLC. Lung dosimetry values vary notably between different definitions of functional lung.

Spect-guidance to Reduce Radioactive Dose to Functioning Lung for Stage III Non-small Cell Lung Cancer

To investigate the treatment effect of additional information obtained by single photon emission computed tomography (SPECT) lung perfusion imaging (LPI) in the radiotherapy planning process for patients with stage III non-small cell lung cancer (NSCLC). 39 patients with stage III NSCLC were enrolled. Gross tumor volume (GTV) was outlined by SPECT/CT images, SPECT-LPIs being used to define functional lung (FL) and non-functional lung (NFL) regions. Two sets of IMRT plans were designed to deliver 64Gy to PTV. One was a regular IMRT plan using CT images only (Plan 1), and the other was a corresponding IMRT plan using co-registered images (Plan 2). FLVx (the % volume of functional lung receiving ≥x Gy) and WLVx (% volume of whole lung to receive ≥x Gy) were compared by paired Student's t test. Kendalls correlation was used to analyze the factor (s) related with the FLV20 decrease. Compared with plan 1, both WLVx and FLVx were decreased in plan 2. WLV10, WLV15, WLV20, WLV25, WLV30 and WLV35 decreased 9.7%, 13.8%, 17.2%, 12.9%, 9.8% and 9.8%, and FLV10, FLV15, FLV20, FLV25, FLV30 and FLV35 decreased 10.8%, 14.6%, 17.3%, 14.5%, 14.5% and 10.5%. FLVx decreased significantly compared with WLVx. There were significant differences in WLV10, WLV15, WLV20, WLV25, WLV3 and FLV10, FLV15, FLV20, FLV25, FLV30 between plan 1 and plan 2 (P=0.002, 0.000, 0.000, 0.005, 0.027 and 0.002, 0.000, 0.000, 0.006, 0.010). According to Kendall correlation analysis, NFL had a negative relation with the percentage FLV20 decrease (r=-0.559, P<0.01), while the distance of PTV and NFL center had a significantly positive relation with the percentage of FLV20 decrease (r=0.768, P<0.01). Routine use of SPECT-LPI for patients undergoing radiotherapy planning for stage III NSCLC appears warranted.

SU-D-BRB-01: 4D-CT Lung Ventilation Images Vary with 4D-CT Sorting Techniques.

4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques. Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared. In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.79±0.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase. 4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

SU-FF-T-517: Dose Painting by Numbers Using Single Photon Emission Computed Tomography with Intensity-Modulated Radiotherapy to Reduce Dose to Highly Functional Lung Region for Lung Cancer Patients

Purpose: To reduce doses to highly functional lung region for lungcancer patients by dose painting by numbers using single photon emission computed tomography with intensity‐modulated radiotherapy.Method and Materials: A non‐small‐cell lungcancer(NSCLC) patient treated in our institute was randomly selected for this study. Two cost functions (referred to Bio_function and nonBio_function) for IMRT optimization were built as research plug‐ins by incorporating and not incorporating single photon emission computed tomography(SPECT)image data of the lung into the optimization algorithm in Pinnacle treatment planning system. Two strategies were evaluated: 1) the IMRT plan with Bio_function (SPECT_Plan); 2) the IMRT plan with nonBio_function (nonSPECT_Plan). Results: The difference of prescription dose coverage of PTV between the two plans was within 1%. Compared to the nonSPECT_Plan, the SPECT_Plan had −0.6 Gy difference of maximum dose for the spinal cord, −1.2% of V55 for the esophagus, 1.0% of V50 for the heart, −2.8%, −3.5%, −3.4%, and −2.8% for V5, V10, V20, and V30 of the total lung, respectively. The mean doses to highly functional lung regions F50 and F90 (defined as the lung regions with perfusion levels above 50 and 90 percent of the maximum perfusion level in the lung, respectively) were reduced by 2.6 Gy and 3.1 Gy in the SPECT_Plan compared to those in the nonSPECT_Plan, respectively. V5, V10, V20, and V30 for F50 lung were reduced by 4.1%, 5.9%, 6.0%, and 5.4%, and by 5.4%, 9.3%, 5.7%, and 7.0% for F90 lung, respectively. Conclusion:Dose painting by numbers using SPECTimage with IMRT could reduce doses to highly functional lung region for lungcancer patients, thus may improve treatment outcome.

SU-FF-T-151: Perfusion-Based Plan Optimization for Lung Cancer Using An Anatomy-Based Aperture Inverse Planning System

Purpose: To implement SPECT‐based plan optimization in an anatomy‐based aperture inverse planning system (IPS) for the avoidance of functional pulmonary regions for cases of lungcancer.Method and Materials: The IPS allows simultaneous optimization of beam orientations and weights from apertures defined by an anatomy‐based segmentation. SPECT perfusion information has been integrated in the dose‐volume‐based cost function of the inverse planning system through a voxel‐by‐voxel linear spatial modulation of the importance factors (IFs) according to local perfusion score. For two cases of lungcancer, plans have been generated by the IPS using four non‐coplanar incidences (gantry and couch angles optimized) using a purely anatomical approach and the SPECT‐based approach. Planning target volume (PTV) coverage and lung avoidance (both volumetric and functional) have been compared. Results: Maximum dose to PTV is usually increased when increasing importance of functional lung regions in the optimization, creating boost regions. For the first case, the functional volume of lung receiving 20 Gy (F20) decreases from 28.4% to 22.0% while the mean lung perfused dose (MpLD) decreases from 16.5 Gy to 13.7 Gy. For the second case, the F20 does not vary (26.5%) and the MpLD decreases from 17.4 Gy to 16.6 Gy. All plans produced are simpler than typical IMRT plans, with few segments (5 or 10) and few monitor units (range 285–375) used. Conclusions: The system allows generation of simple aperture‐based IMRT plans with the addition of functional lung sparing when considering SPECT‐based information. However, the extent of the benefit is patient‐dependant and varies according to the perfusion pattern and proximity of other critical structures to the PTV. Boost regions created by the redistribution of dose might prove useful in the context of dose escalation in lung irradiation.

A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung

Single photon emission computed tomography (SPECT) provides a map of the spatial distribution of lung perfusion. Thus, SPECT guidance can be used to divert dose away from higher-functioning lung, potentially reducing lung toxicity. We present a methodology for achieving this aim and test it in intensity-modulated radiotherapy (IMRT) treatment-planning. IMRT treatment plans were generated with and without SPECT guidance and compared for 5 patients. Healthy lung was segmented into four regions on the basis of SPECT intensity in the SPECT plan. Dose was sequentially allowed to the target via regions of increasing SPECT intensity. This process results in reduction of dose to functional lung, reflected in the dose-function histogram (DFH). The plans were compared using DFHs and F(20)/F(30) values (F(x) is the functional lung receiving dose above x Gy). In all cases, the SPECT-guided plan produced a more favorable DFH compared with the non-SPECT-guided plan. Additionally, the F(20) and F(30) values were reduced for all patients by an average of 13.6% +/- 5.2% and 10.5% +/- 5.8%, respectively. In all patients, DFHs of the two highest-functioning SPECT regions were reduced, whereas DFHs of the two lower-functioning regions were increased, illustrating the dose "give-take" between SPECT regions during redistribution. SPECT-guided IMRT shows potential for reducing the dose delivered to highly functional lung regions. This dose reduction could reduce the number of high-grade pneumonitis cases that develop after radiation treatment and improve patient quality of life.